Thrombosis Research 133 (2014) 743–749
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Regular Article
Cost-Effectiveness Analysis of Extended Duration Anticoagulation with Rivaroxaban to Prevent Recurrent Venous Thromboembolism Craig I. Coleman a,⁎, Brendan L. Limone a, Brahim K. Bookhart b, Samir H. Mody b, Edith A. Nutescu c a b c
University of Connecticut School of Pharmacy, Storrs, CT, USA Janssen Scientific Affairs, Raritan, NJ, USA University of Illinois at Chicago College of Pharmacy and University of Illinois Hospital and Health Sciences System, Chicago, IL; USA
a r t i c l e
i n f o
Article history: Received 26 December 2013 Received in revised form 29 January 2014 Accepted 4 February 2014 Available online 11 February 2014 Keywords: Venous thromboembolism Extended treatment Anticoagulation Rivaroxaban Cost-effectiveness analysis Markov model
a b s t r a c t Introduction: Extended duration anticoagulation with rivaroxaban for an additional 6–12 months can reduce recurrent venous thromboembolic events (VTE) compared to placebo by ~82%, but at the detriment of increased bleeding. We sought to estimate the cost-effectiveness of extended duration prophylaxis of recurrent VTE with rivaroxaban. Material and Methods: A Markov model was developed to estimate the cost-effectiveness of extended duration rivaroxaban, 20 mg daily, compared to placebo using a Medicare perspective, a one-month cycle length and a 40-year time horizon. The model assumed a cohort of 58-year-old patients who had already completed an initial 6–12 months of anticoagulation with rivaroxaban or a vitamin K antagonist; and whom prescribers had clinical equipoise with respect to the need for continued anticoagulation. Data sources included EINSTEIN-Extension and other published studies of VTE. Outcomes included direct treatment costs (in 2013US$), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Results: Extended duration rivaroxaban resulted in higher treatment costs ($22,645 vs. $22,083) but yielded greater QALYs (16.167 vs. 16.134) as compared to placebo; corresponding to an ICER of $17,030/QALY gained. Our model was most sensitive to the baseline risk of bleeding and recurrent VTE, the hazard ratio of developing a recurrent event while on rivaroxaban and time horizon. Monte Carlo Simulation suggested rivaroxaban would be cost-effective in 66% of 10,000 iterations, assuming a willingness-to-pay threshold of $50,000/QALY. Conclusion: Despite the cost of rivaroxaban and an increased risk of bleeding, extending VTE treatment for an additional 6–12 months with rivaroxaban was found cost-effective compared to the placebo over a 40-year time horizon. © 2014 Elsevier Ltd. All rights reserved.
Introduction Rivaroxaban is a factor Xa inhibitor indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the reduction in the risk of recurrence of DVT and of PE. The EINSTEIN-Extension trial compared rivaroxaban 20 mg once daily with placebo in patients who completed their standard treatment course of anticoagulation (3–12 months in duration) after an index venous thromboembolism (VTE), in whom there was clinical equipoise with respect to the need for continued anticoagulation [1]. After 6–12 additional months of treatment, rivaroxaban reduced the risk of recurrent VTE by 82% [95% confidence interval (CI) = 61%-91%; or 8
⁎ Corresponding author at: University of Connecticut, University of Connecticut/ Hartford Hospital, Evidence-Based Practice Center, 80 Seymour Street, Hartford, CT 06102–5037, USA. Tel.: +1 860 545 2096; fax: +1 860 545 2277. E-mail address:
[email protected] (C.I. Coleman).
http://dx.doi.org/10.1016/j.thromres.2014.02.006 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
events (1.3%) in the rivaroxaban group vs. 42 (7.1%) in the placebo group] but increased non-major bleeding complications [non-major bleeding occurred in 32 patients (5.4%) in the rivaroxaban group and in seven patients (1.2%) in the placebo group]. These results suggest that rivaroxaban is effective for patients requiring extended duration secondary prevention of VTE; however, the cost-effectiveness of this approach has not yet been evaluated. Consequently, the objective of our study was to estimate the cost-effectiveness of extended duration prophylaxis of recurrent VTE with rivaroxaban compared to no therapy (placebo). Materials and Methods A Markov model was developed to assess the cost-effectiveness of extended duration anticoagulation with rivaroxaban for the prevention of recurrent VTE. Markov models offer advantages (over other modeling methods such as decision tree analysis) when a problem involves risk that continues over time, when the timing of events is important, and
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when key events can occur more than once [2]. Markov models frame the decision in terms of heath states and follows patients as they transition from one state to another accruing related costs and consequences. Fig. 1 depicts the structure of our extended duration VTE treatment model. To best match the scenario under which extended duration rivaroxaban has been studied [1], our base-case analysis assumed a cohort of 58-year-old patients (both men and women) who had already received 6–12 months of anticoagulation with rivaroxaban or a vitamin K antagonist (VKA) after suffering either a PE or an acute symptomatic DVT, and in whom there was clinical equipoise (genuine uncertainty about the most beneficial treatment) with respect to the need for continued anticoagulation. As in the EINSTEIN-Extension trial [1], patients with a creatinine clearance b30 mL/minute, significant liver disease or liver enzymes 3 times the upper limit of normal, bacterial endocarditis, active bleeding or at high-risk of bleeding, markedly elevated blood pressure, and those taking concomitant medications that inhibit or induce the CYP450 enzyme system and/or alter the P-glycoprotein transport system, such as ketoconazole, fluconazole, erythromycin, ritonavir, rifampin, and phenytoin, were excluded. The model assigned patients to receive either rivaroxaban 20 mg daily or placebo for an additional 6–12 months. All patients started and remained in the “well” state until one of the following events occurred: DVT or PE, DVT with post-thrombotic syndrome (PTS), extracranial major bleed (assumed to be gastrointestinal (GI)), intracranial hemorrhage (ICH) or death. The base-case model assumed: 1) if patients in either
treatment arm experienced a recurrent VTE at any point, indefinite anticoagulation was initiated and a vena cava filter (VCF) was placed; 2) after any major bleed (GI or ICH), anticoagulation was permanently discontinued; 3) patients could temporarily discontinue anticoagulation for one month due to clinically relevant non-major bleeding; 4) patients with a history of ICH were assumed to have an increased mortality rate; 5) patients experiencing a recurrent DVT had an inherent risk of PTS; 6) patients had an increased risk of recurrent VTE during the first year following discontinuation of anticoagulation and a lower risk for subsequent years; 7) given a VTE, patients with a VCF already in place had a higher risk of DVT; 8) we assumed after patients discontinued anticoagulation, no further treatment effect from these drugs would occur. Thus, all event rates in the Markov model were assumed the same for patients who had been on any of the strategies, with the only difference being the proportion of patients in each Markov health state, and 9) patients were not taking any other anticoagulant therapy during the study and had no contraindication to receiving rivaroxaban. Transition probabilities between health states were derived using standard methods [2] from the EINSTEIN-Extension trial data [1] and other sources identified through the Tufts Cost-Effectiveness Analysis registry and a Medline database search [3–19] (Table 1). Age-adjusted all-cause mortality rates were derived from the United States Census Bureau Life Tables [20]. The analysis was conducted from a Medicare/ United States payer perspective, and thus considered only drug acquisition costs and direct
Fig. 1. Schematic Representation of the Markov Model. Patients received either rivaroxaban or placebo. “M” represents the Markov node with 16 health states depicted in the figure for each of the treatment options. In addition, seven AC temporary disruption and eight re-initiation health states were also modeled (not depicted in figure). All potential health states were identical for each treatment option. All patients remained in the “Well” state until an event (PE or DVT, DVT with PTS, major bleed, ICH or death) occurred. This model also included health states for patients who developed recurrent VTE, who qualified for unlimited duration of anticoagulation. AC = anticoagulation; DVT = deep venous thrombosis; rVTE = recurrent VTE; ICH = intracranial hemorrhage; Mo = month; PE = pulmonary embolism; PTS = post-thrombotic syndrome; VTE = venous thromboembolism.
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Table 1 Base-Case Variables and Ranges for the Markov Model. Variable Costs in 2012 USD Rivaroxaban (annualized) Warfarin including INR monitoring (annualized) Event costs PE DVT VCF placement ICH GI bleed Office visit Permanent costs (annual) Post-ICH care PTS care Utility Estimates (annual) Healthy on rivaroxaban Healthy on warfarin Healthy on placebo Post-ICH Disutility Estimates for Acute Complications (annual) PTS PE (for one cycle) DVT (for one cycle) GI bleed (for 2 weeks) Probabilities (Event Rates) HR of rVTE on rivaroxaban Annual rate of rVTE Proportion of rVTE that are PE Proportion of PE that result in death Proportion of DVT that result in death Proportion of DVT that result in PTS RR of PE with VCF Annual rate of rVTE after anticoagulation is stopped (Year 1) Annual rate of rVTE after anticoagulation is stopped (Year 2+) HR of bleed on rivaroxaban Annual rate of bleed Proportion of bleeds that are major Proportion of major bleeds that are ICH Proportion of ICH that are fatal Proportion of GI Bleeds that are fatal Annual rate of death following ICH Discount rate (%)
Base-Case
Range
Reference
3,044 408
2,283 - 3,805† 204 – 600⁎
Per Janssen Pharmaceuticals 25
9,727 6,003 2,796 28,177 10,346 73
4,864 - 14,591⁎ 3,002 - 9,006⁎ 1,398 - 4,194⁎ 14,088 - 42,266⁎ 5,126 - 15,518⁎ 44 – 107⁎
16,27 16,27 16,27 16,27 16,27 16,27
17,994 428
8,997 - 27,004⁎ 214 – 642⁎
3,29 16,27
0.998 0.988 1 0.6
0.996 - 1 0.92 - 1 0.998 - 1 0.02 - 1
1,23 24 24 31
−0.05 −0.37 −0.12 −0.16
0 to −0.21 −0.14 to −0.64 0 to −0.326 −0.12 to −0.2
31 34 34-36 25,32,33
0.18 7.1% 34% 11.8% 3% 17% 0.5 5.6%
0.09 - 0.39 5.3% - 8.5% 17% - 51% 5.3% - 28% 0% - 5% 14% - 24% 0.19 - 1.33 2% - 11%
1 1 1 1,6,7,13 8 10 15 13,14,16-18
3.5%
2% - 7%
13,14,16-18
5.19 1.2% 10% 7.5% 40% 1% 18% 3%
2.3 - 11.7 0% - 10% 5% - 15% 5% - 20% 15% - 71% 0% - 1% 17% - 31.8% 0% - 5%
1 1 1 1,11 1,11 9,11,12,19 3 37
DVT = deep venous thrombosis; GI = gastrointestinal; HR = hazard ratio; ICH = intracranial hemorrhage; INR = international normalized range; PTS = post-thrombotic syndrome; PE = pulmonary embolism; RR = relative risk; USD = United States dollar; VCF = vena cava filter; rVTE = recurrent venous thromboembolism -– = not applicable. † =lower and upper plausible ranges represent the base-case value ±25%. ⁎ = lower and upper plausible ranges represent the base-case value ±50%.
costs resulting from inpatient treatment of major complications (VTE or bleeding), procedures and office visits, as well as costs associated with each permanent health state (post-ICH and/or post-PTS care). The cost of rivaroxaban therapy was calculated from the wholesale acquisition cost (WAC). Direct costs from each complication were calculated from expected billing codes (using national average Medicare payment/ reimbursement rates without any adjustment) or from previously published studies [21–24]. Each inpatient treatment included the cost of the specific diagnosis-related group (DRG) as well as costs for admission (current procedural terminology (CPT) code 99222), daily costs (CPT code 99232) adjusted for average length of stay for each complication, and discharge costs (CPT code 99239) [25,26]. If applicable, costs for any lab interpretations (CPT code 77012) or filter placement (CPT code 37191) were added. DRG codes were used to determine diagnosis-specific costs for PE with major complications and comorbidities (MCC) (DRG 175), DVT with MCC (DRG 294), ICH with MCC (DRG 064), and GI hemorrhage with MCC (DRG 377). The cost for an outpatient office visit (CPT code 99203) after a clinically relevant non-major bleed was also integrated into the model. Costs associated with permanent health states were estimated based upon previously published studies, and included direct costs for post-ICH and/or post-
PTS care [14,27,28]. Costs were inflated to 2013 US dollars (when applicable) using the Bureau of Labor Statistics’ Consumer Price Index for Medical Care [29]. Quality-adjusted life-years (QALYs) were calculated by multiplying life years by utility scores derived from previously published literature. The disutility for rivaroxaban was assumed to be small due to the drug’s once daily oral profile and the lack of required monitoring [29,30]. Permanent disutilities were assigned to patients entering the ICH and/or PTS health states [31]; while one-time disutilities were assigned to patients who experienced acute complications such as GI bleeds [24,32,33] or recurrent VTE [34–36]. The model was run separately for the rivaroxaban and placebo treatment strategies, and used to estimate total costs (in 2013 US$), QALYs and incremental cost-effectiveness ratios (ICERs) over a 40-year (life-time) time-horizon using a one-month cycle length. The 40-year time horizon was used in order to capture downstream costs and consequences (i.e., the cost and disutility of PTS) related to the decision to treat or not treat patients, but in no way implies all patients were treated or survived for this entire duration of time). Costs and QALYs were discounted at a 3% annual rate [37]. The model was built and analyzed in TreeAge Pro 2008 (TreeAge Software Inc., Williamstown, MA).
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To assess model robustness, one-way sensitivity analyses, scenario analyses and Monte Carlo simulations (MCS) were performed. Oneway sensitivity analyses were run for all variables at a priori defined low and high plausible ranges. The lower and upper plausible ranges were typically derived by 1) adding or subtracting 25% or 50% from the base-case value (costs); 2) using the lower and upper limits of reported or calculated 95% confidence intervals (rates and proportions); 3) or using assorted values obtained from published sources (utilities and disutilities). Scenario analyses were run whereby the model time horizon was varied between 40-years (base-case) and 5-years, in 5-year increments, and when assuming 50% of patients experiencing a recurrent VTE while on rivaroxaban or placebo would receive a VKA preferentially (adjusted to consider the cost of international normalized ratio monitoring and warfarin at a dose of 5 mg/day and an excess disutility of being on warfarin). MCS was carried out based on 10,000 iterations, with all variables simultaneously and randomly varied across set distributions. Triangle distributions (defined by a likeliest, low and high values) were utilized for all variables in MCS since the true nature of variance for these variables are not well understood, and the triangle distribution (when used correctly) does not violate the requirements of any variable (i.e., costs cannot be less than $0 and probabilities and utilities must range between 0 and 1). Results of the MCS are reported as a cost-effectiveness acceptability curve (CEAC). We followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement in reporting this cost-effectiveness analysis [38]. Results Extended duration treatment with rivaroxaban resulted in a higher treatment costs ($22,645 vs. $22,083) but yielded greater QALYs (16.167 vs. 16.134) as compared to placebo; corresponding to an ICER of $17,030/QALY gained (Table 2). Upon one-way sensitivity analysis, the model was found to be most sensitive to changes in the baseline risk of bleeding and recurrent VTE and the hazard ratio of developing a recurrent event while on rivaroxaban (Table 3). Scenario analysis demonstrated the cost/QALY gained with extended duration rivaroxaban increased as the model’s time horizon decreased from 40- to 5-years; surpassing the $50,000/ QALY gained willingness-to-pay threshold between model years 10 Table 2 Base-Case and Scenario Analysis.
Table 3 One Way Sensitivity Analysis. Variable
Low ICER⁎ (US$)
High ICER⁎ (US$)
Spread (US$)
Annual rate of bleed Annual rate of rVTE Discount rate HR of rVTE on rivaroxaban Proportion of PE that result in death Cost of rivaroxaban Proportion of DVT that are fatal Proportion of rVTE that are PE HR of bleed on rivaroxaban Disutility of PTS Cost of DVT Proportion of bleeds that are major Proportion of bleeds that are ICH Cost of PE Proportion of GI bleeds that are fatal Cost of VCF placement Proportion of DVT that result in PTS RR of PR with a VCF Cost of PTS Utility of rivaroxaban Disutility of DVT Utility of Placebo Cost of GI bleed Disutility of PE Cost of ICH Cost of post-ICH care Disutility of ICH Cost of an office visit Proportion of ICH that are fatal Annual rate of death following ICH Disutility of GI bleed
1,3926 6,241 1,865 11,324 10,494 10,464 14,188 14,145 15,043 12,768 14,841 15,344 16,288 15,473 16,546 15,894 15,763 15,792 16,283 16,426 16,521 16,426 16,567 16,601 16,667 16,686 16,688 16,688 16,690 16,691 16,694
82,780 42,961 27,808 35,385 23,842 22,925 23,825 20,661 21,231 18,470 18,547 18,167 19,069 17,916 18,171 17,495 17,122 17,060 17,441 17,308 17,133 17,030 17,157 17,110 17,058 17,039 17,039 17,038 17,033 17,031 17,031
68,854 36,720 25,943 24,061 13,348 12,461 9,637 6,516 6,188 5,702 3,706 2,824 2,781 2,443 1,625 1,601 1,359 1,267 1,158 882 612 604 590 509 391 353 351 350 343 340 337
DVT = deep vein thrombosis; GI = gastrointestinal; HR = hazard ratio; ICER = incremental cost-effectiveness ratio; ICH = intracranial hemorrhage; PE = pulmonary embolism; PTS = post-thrombotic syndrome; rVTE = recurrent venous thromboembolism; VCF = vena cava filter. ⁎ ICER at the lowest/highest end of variable sensitivity range.
and 11, and $100,000/QALY gained between years 6 and 7. When 50% of patients experiencing a recurrent VTE were prescribed warfarin instead of rivaroxaban, the ICER for rivaroxaban was $31,972/QALY. MCS suggested rivaroxaban would be cost-effective in 66% of 10,000 iterations, assuming a willingness-to-pay threshold of $50,000/QALY (Fig. 2). Discussion
Treatment Strategy 40 Year Time Horizon (Base-case) Rivaroxaban Placebo 35 Year Time Horizon Rivaroxaban Placebo 30 Year Time Horizon Rivaroxaban Placebo 25 Year Time Horizon Rivaroxaban Placebo 20 Year Time Horizon Rivaroxaban Placebo 15 Year Time Horizon Rivaroxaban Placebo 10 Year Time Horizon Rivaroxaban Placebo 5 Year Time Horizon Rivaroxaban Placebo
Costs (US$)
QALYs
ICER (US$)
22,645 22,083
16.167 16.134
17,030 —
22,251 21,685
16.016 15.982
16,918 —
21,179 20,600
15.574 15.541
17,697 —
19,157 18,543
14.665 14.634
19,703 —
16,186 15,550
13.176 13.148
24,119 —
12,490 11,675
11.031 11.007
33,627 —
8,473 7,445
8.170 8.152
56,562 —
4,734 3,374
4.522 4.512
139,811 —
ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.
This Markov model evaluating life-time costs and QALYs associated with extended duration prophylaxis of recurrent VTE suggests rivaroxaban 20 mg once daily is cost-effective compared to no extended treatment in the United States (assuming a willingness-to-pay threshold of $50,000/QALY gained), starting approximately 10-years after treatment initiation. While the amount of QALYs gained with the use of rivaroxaban was small (0.033), it is important to note, MCS suggested rivaroxaban would likely be cost-effective at this threshold in about two-thirds of iterations run. Controversy exists around the need, optimal duration and specific agent for extended duration prophylaxis of recurrent VTE. For patients with unprovoked VTE and low-to-moderate risk of bleeding, current consensus guidelines [39] recommend extended oral anticoagulation beyond the initial 3-months of therapy. Moreover, aspirin [40,41] and the novel oral anticoagulants, rivaroxaban [1], dabigatran [42] and apixaban [43], have all been evaluated for extended duration prophylaxis after an initial period of therapy, and now offer an alternative to warfarin and other vitamin K antagonists (VKAs). While each of these agents have been compared to placebo for extended VTE treatment [1,6,7,13,4,18,40–43], only dabigatran [42] has been compared to warfarin as part of a head-to-head randomized trial. A Bayesian
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100%
Percentage of Time Cost-effective
90% 80% 70% 60% 50% 40% 30% 20%
Rivaroxaban
10% 0%
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
80,000
90,000 100,000
Willingness-to-pay Threshold (US$) Fig. 2. Cost-Effectiveness Acceptability Curve.
network meta-analysis by Castelucci and colleagues [44] compared the novel oral anticoagulants, aspirin and low-intensity VKA therapy to adjusted-dose VKA therapy, and found no statistically significant difference in the odds of recurrent VTE [95% credible intervals (CrI) for the odds ratios (ORs) crossed 1.0] for any of the novel agents, but an increased risk of recurrent events with aspirin (OR = 9.14, 95%CrI = 3.66-24.91) and low-intensity VKA therapy (OR = 3.98, 95% CrI = 1.73-9.74). In respect to major bleeding, the meta-analysis reported adjusted-dose VKA therapy was associated with the greatest risk (OR = 5.24, 95%CrI = 1.78-18.25); and also concluded that in general the risk of fatal bleeding in these patients is rare. However, in addition to the efficacy and safety data presented above, we suggest additional factors including individual patient-risk factors, cost, lifestyle modifications, burden of laboratory monitoring and patient values and preferences be taken into consideration when making recommendations to patients regarding the need and specific anticoagulant used for extended treatment. Two Markov models [45,46] have shown rivaroxaban to be an economically dominant strategy (less costly; more effective) for acute treatment and short-term prevention of VTE recurrence. However, no prior economic analysis evaluating the cost-effectiveness of rivaroxaban for extended duration prophylaxis has been published; and only a paucity of economic data evaluating extended duration use of other anticoagulats to prevent recurrent VTE is available. Aujesky and colleagues [4] modeled the cost-effectiveness of oral anticoagulation strategies after a first idiopathic VTE event and found longer initial adjusted-dose VKA therapy to be cost-effective in younger patients and 3-months of anticoagulation preferred in the elderly; but only did so by comparing different durations of therapy starting from the index event, and thus factored in all the costs and outcomes associated with it. In addition, due to the age of the analysis, the authors used VKA treatment costs (drug acquisition plus monitoring) that are higher than in our analysis. Eckman and colleagues [47] also developed a decisionanalytic model to assess the cost-effectiveness of extended duration treatment of VTE with a VKA, but only evaluated it in the context of factor V Leiden testing. As a result, it is difficult to compare the results of this model to one conducted in patients with true clinical equipoise for extended anticoagulation. Finally and most recently, a Markov model-based cost-effectiveness analysis centered upon the Aspirin for the Prevention of Recurrent Venous Thromboembolism (WARFASA) trial data found extending the duration of prophylaxis with aspirin in patients suffering their first episode of unprovoked VTE would result in cost savings and additional QALYs lived ($12,635 vs. $13,877 for aspirin and placebo, respectively, with corresponding QALY estimates of 15.123 and 15.020) [5]. However, when the less favorable data from
the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trial is also considered [41], the above-mentioned meta-analysis by Castelucci [44] suggests aspirin is inferior to warfarin and the novel oral agents in preventing recurrent VTE. There are some limitations to consider when putting the results of our model into context. First, many of the key transition probabilities used in the Markov model were extrapolated from a single, randomized controlled trial (the EINSTEIN-Extension trial) and we needed to extrapolate the results of this trial which treated patients for 6–12 months to our model’s longer time horizon [1]. Secondly, as in any costeffectiveness analysis, special attention should be paid to the choice of a comparator. In our model, the comparison was made to placebo (no therapy); however, other alternatives do exist [39–44]. We did not attempt to compare rivaroxaban to alternative therapies because of the lack of head-to-head trial data, instability of comparative effect estimates stemming from available network meta-analyses, and the concerns about the comparability of trial populations [1,39–44]. Thirdly, there is significant disagreement regarding when to place VCFs. While many national guidelines have made recommendations about appropriate indications for VCFs, there are significant differences among them [39,48,49]. Our model assumed patients experiencing a recurrent VTE while on adequate anticoagulation received a VCF; which is in line with American Heart Association and Society of Interventional Radiology guidance. However, it is worth noting, the American College of Chest Physicians guidelines do not make this recommendation. Fourthly, we acknowledge that not all clinicians and decision-makers will agree with all our model’s assumptions. Such assumptions might include our use of constant rates of recurrent VTE and major bleeding over time, or our decision to stop anticoagulation in the event of a major bleed. This latter assumption seemed particularly reasonable; however, given the EINSTEIN-Extension trial only enrolled patients in whom there was genuine uncertainty about the need for continued anticoagulation [1]. Next, our model focused on direct medical costs only and did not include indirect (lost productivity) and other types of potentially relevant costs (i.e., informal caregiver costs, etc.). That being said, the inclusion of these costs would likely favor rivaroxaban because of the agents ability to prevent hospitalizations and lost work time due to VTE recurrence, as well as prevent downstream complications of VTE such as PTS. Finally, users of this economic analysis should remember the determination of whether an intervention is costeffective or not must be viewed in context of the specific willingnessto-pay threshold used [37]. While we utilized a $50,000/QALY threshold because it has been reported in the majority of economic analyses using a United States healthcare perspective; other threshold values (i.e., $100,000/QALY) exist and have been advocated [50–52]. Consequently,
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the conclusions of our cost-effectiveness analysis and sensitivity analyses may be interpreted differently, depending on what willingnessto-pay threshold is considered acceptable by a decision-maker. In conclusion, despite the cost of rivaroxaban and an increased risk of bleeding, extending VTE treatment for an additional 6–12 months with rivaroxaban was found cost-effective assuming a willingnessto-pay threshold of b $50,000/QALY gained for a time horizon of 40 years, compared to the placebo. Funding This work was supported by Janssen Scientific Affairs, Raritan, NJ, USA. The authors maintained full control over the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript. Janssen Scientific Affairs reviewed the final manuscript prior to submission. Dr. Coleman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of Interest Statement Drs. Coleman and Nutescu have received grant funding from Janssen Scientific Affairs, LLC, Raritan, New Jersey, USA, and Dr. Coleman is a member of Janssen’s speaker’s board for Xarelto. Dr. Nutescu is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL112908. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Limone has no conflicts to disclose. Acknowledgements None. References [1] EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510. [2] Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13:322–38. [3] Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902. [4] Aujesky D, Smith KJ, Roberts MS. Oral anticoagulation strategies after a first idiopathic venous thromboembolic event. Am J Med 2005;118:625–35. [5] Kaur R, Lee S, Zlotnik K, Dabek A, Coleman CI. Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis with Aspirin [abstract]. Circulation 2012;126:A16651. [6] Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901–7. [7] Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, et al. Longterm, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425–34. [8] Kniffin Jr WD, Baron JA, Barrett J, Birkmeyer JD, Anderson Jr FA. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861–6. [9] Patrick AR, Avorn J, Choudhry NK. Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2009;2:429–36. [10] Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1–7. [11] Linkins L, O'Donnell M, Julian JA, Kearon C. Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. J Thromb Haemost 2010;8:2201–7. [12] Collins TC, Petersen NJ, Menke TJ, Souchek J, Foster W, Ashton CM. Short-term, intermediate-term, and long-term mortality in patients hospitalized for stroke. J Clin Epidemiol 2003;56:81–7. [13] Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, et al. Warfarin Optimal Duration Italian Trial Investigators. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003;139:19–25. [14] Agnelli G, Prandoni P, Santamaria MG, et al. Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med 2001;345:165–9.
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